A major focus of our research, and a crucial but poorly understood component of glucocorticoid hormone and steroid hormone action in general, is the determinants of the steroid hormone dose-response curve. Our previous data established that a cis-acting element, called a GME, and its two associated novel binding proteins, can shift the dose-response curve of glucocorticoid receptor (GR) transactivation of a gene under the control of a glucocorticoid response element (GRE). At the same time, the GME increased the residual agonist activity of antiglucocorticoids with at GRE. This shed new light on another conundrum of steroid hormone action: how the same receptor-antagonist complex can display different amounts of residual activity with different genes. To help understand the mechanism for the unusual activities of the GME, we compared the changes in GME activity and GRE action (i.e., the fold induction by GR) caused by modifying several parameters, such as phasing and positioning of the GME relative to the GRE, GRE sequence, and number of GREs. The changes in GME activity did not correlate with those for fold induction from the GRE. We, therefore, conclude that the mechanisms for expression of GME and GRE activities utilize parallel, as opposed to common, pathways. In a different approach, we have already described how varying the levels of GR modify both the dose-response curve and residual agonist activity independent of a GME. This second process is unique in that it does not require the DNA binding domain of GRs that is required for simple GR regulated gene induction. We now find, using a series of mutant GRs, that these disparate transactivation processes appear to utilize identical receptor surfaces and thus may contact the same cofactors. In fact, we have further discovered that both of the above effects of added GR can be reproduced simply by varying the cellular levels of GR- interacting coactivators (TIF2, SRC-1, and AIB1) and comodulator (CBP) in addition to the corepressor (SMRT). This is the first report that glucocorticoid receptors could be a target of the corepressor SMRT. These observations suggest that a new role for cofactors is to help determine the dose-response curve, and partial agonist activity, of GR- steroid complexes. An equilibrium model is proposed in which the ratio of coactivator to corepressor bound to either receptor-agonist or - antagonist complexes regulates the final transcriptional properties. Collectively, these findings contribute to our long term goal of defining the action of steroid hormones at a molecular level and of understanding their role in human physiology. - steroid hormone action, glucocorticoid receptors, transactivation, transcriptional cofactors, dose-response curve, antiglucocorticoids